Dopamine (DA)-containing neurons are centrally involved in the neurobiological processes subserving the detection and transmission of reward. Encoding this signal involves changes in the instantaneous firing rate and thus the discharge pattern of mesotelencephalic DA neurons. Although increases in DA cell activity evoked by stimuli with positive motivational value are initiated by synaptic input(s), the output of these cells (i.e., impulse-dependent DA release) is constrained by several factors. These include the intrinsic electrical properties of the cell as dictated by its complement of voltage and ligand-gated ion channels and short and long-loop homeostatic mechanisms that strive to maintain the "status quo." The interaction between these three factors (afferents, intrinsic properties and homeostatic tone) constrain the activity of DA neurons to one of four distinct modes including single spike and bursting activity and two quiescence states mediated by membrane hyperpolarization or depolarization-induced inactivation of spike generating mechanisms (depolarization block). Under normal conditions, phasic changes in DA cell impulse flow maintain reward-appropriate signaling. Under abnormal conditions, such as those induced by administration of antipsychotic drugs, reward-appropriate signaling may fail. The central premise of the application is that the loss of autoregulatory tone, secondary to functional loss of DA D2 receptors, will increase the cell's responsiveness to excitatory (or disinhibitory) inputs predisposing it to enter a state of depolarization block (Specific Aim #1). It is further speculated that the ensuing loss of impulse-dependent DA release prevents normal transmission of rewarding signaling or predicting stimuli (Specific Aim #2). Finally, it is hypothesized that antipsychotic drugs (APDs) with a receptor binding profile that favors displacement by endogenous DA (so called "fast-off' APDs) will be less likely to induce depolarization block than APDs which bind more tightly and thus at reduced risk for compromising transmission of rewarding stimuli (Specific Aim #3). In order to address these aims, the research proposed in this application combines in vivo electrophysiological methods together with brain stimulation reward techniques to study the relationship between DA cell impulse flow and the neural mechanisms of reward. It is anticipated that the research proposed in this application will provide insight into neurobiological mechanisms responsible for neuroleptic dysphoria and a framework for prospectively designing antipsychotic drugs with a reduced liability for producing negative subjective responses in patients.